Identification of young versus aged proteomes by tagging with non-canonical amino

通过使用非规范氨基酸标记来鉴定年轻与老年蛋白质组

• 批准号: 8928694
• 负责人: Irina M Conboy
• 金额: $ 15.6万
• 依托单位: UNIVERSITY OF CALIFORNIA BERKELEY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-30 至 2016-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8928694
• 关键词: Accounting; Age; Aging; Aging-Related Process; Amino Acids; Amino Acyl-tRNA Synthetases; Animals; Area; Biochemical; Biological Assay; Blood; Blood Circulation; Cardiovascular system; Cell Transplants; Cells; Chimerism; Collaborations; Cytomegalovirus; Data; Databases; Development; Economics; Experimental Models; Fractionation; Genetic; Goals; Health; Hippocampus (Brain); Human; Individual; Internal Ribosome Entry Site; Intervention; Knowledge; Label; Laboratories; Longevity; Maintenance; Mammalian Cell; Mammals; Mass Spectrum Analysis; Metabolic; Methionine-tRNA Ligase; Modeling; Molecular; Molecular Genetics; Mus; Muscle; Natural regeneration; Organ; Organism; Outcome Study; Parabiosis; Performance; Proteins; Proteome; Proteomics; Publishing; Rejuvenation; Research; Research Personnel; Resistance; Role; Serum; Serum Proteins; Skeletal Muscle; Stem cells; System; Testing; Therapeutic; Time; Tissues; Transgenic Mice; Translations; Work; aged; base; combinatorial; high reward; high risk; improved; in vivo; interest; muscle regeneration; mutant; myogenesis; neurogenesis; novel; prospective; regenerative; repaired; social; success; tissue regeneration; tissue repair

DESCRIPTION (provided by applicant): Accommodating an aging world will pose significant economic and social challenges and will ultimately call for both paradigm-shift in our understanding, and biomedical interventions into the aging process. Extensive data demonstrate that when the systemic niches of organ stem cells are biochemically rejuvenated, stem cells endogenous to multiple old organs engage in productive tissue regeneration. Importantly, the old circulatory milieu rapidly and significantly inhibits the regenerative performance of endogenous stem cells in young organs. This proposal uses what is known about the role of the circulatory milieu in the rejuvenation of aged tissue repair, with the goal o determining the key molecular mechanisms that are responsible for the phenomena of heterochronic parabiosis. Until recently, it was technologically impossible to specifically label and interrogate the proteome of one animal in the setting of heterochronic parabiosis; however the development of cell-selective metabolic labeling of proteins with non-canonical amino acids via expression of mutant aminoacyl-tRNA synthetases in mammalian cells by the co-PI (David Tirrell) enabled this paradigm shifting approach. This high-risk high-reward project becomes feasible due to the united efforts, areas of expertise and experimental models of the Conboy and Tirrell research groups. The Conboy team has proficiency in studies of heterochronic parabiosis and characterization of the effects of defined factors on tissue regenerative capacity, whereas the Tirrell laboratory has pioneered and time-resolved and cell-selective proteomics. The paradigm changing outcomes of these studies are many fold: (1) revealing the "youthful" pro-regenerative and "aged" inhibitory proteomes of blood serum, (2) uncovering the mechanisms by which the circulation influences the regenerative performance of organ stem cells in muscle and brain/hippocampus; (3) generating a comprehensive data-base that is required for understanding the genetics of aging and importantly, (4) identifying novel ways to rejuvenate multiple organs and extend healthy life span via systemic administration of defined molecules that emulate the physiologically young blood circulation.

描述（由申请人提供）：应对老龄化世界将带来重大的经济和社会挑战，并最终要求我们的理解发生范式转变，并对老龄化过程进行生物医学干预。大量的数据表明，当器官干细胞的系统小生境被生化再生时，多个旧器官的内源性干细胞参与生产性组织再生。重要的是，旧的循环环境迅速并显著地抑制了年轻器官中内源性干细胞的再生性能。该建议使用已知的循环环境在老化组织修复的再生中的作用，目标是确定负责异时共生现象的关键分子机制。直到最近，在异时共生的环境中特异性标记和询问一种动物的蛋白质组在技术上是不可能的;然而，通过共同PI（大卫蒂雷尔）在哺乳动物细胞中表达突变型氨酰-tRNA合成酶，开发了具有非经典氨基酸的蛋白质的细胞选择性代谢标记，使得这种范式转变方法成为可能。由于Conboy和Tirrell研究小组的共同努力，专业领域和实验模型，这个高风险高回报的项目变得可行。Conboy团队精通异时共生研究和确定因素对组织再生能力影响的表征，而Tirrell实验室则开创了时间分辨和细胞选择性蛋白质组学。这些研究的范式改变的结果是多方面的：（1）揭示血清中“年轻”的促再生和“衰老”的抑制性蛋白质组，（2）揭示循环影响肌肉和脑/海马中器官干细胞再生性能的机制;（3）生成理解衰老遗传学所需的全面数据库，重要的是，（4）通过全身施用模拟生理学上年轻的血液循环的限定分子，确定使多个器官恢复活力并延长健康寿命的新方法。